COMMENTARY

Androgen Replacement Therapy in the Aging Male—A Critical Evaluation

Recent years have seen an increasing interest in the study of the aging male, with a particular interest in the problem of whether so-called rejuvenating hormones and, more specifically, androgens can improve quality of life, counteract progressive skeletal muscle loss and strength, prevent falls
and fractures, prolong independent living, and reduce the dependence on medical care.

Almost a decade has elapsed since the first studies on androgen supplementation in elderly men were published (1,2) and, in the view of the persisting controversies concerning this problem as well as the increasing public interest for rejuvenating hormones, it may be indicated to evaluate critically the clinical relevance of the relative androgen deficiency in elderly males, the diagnostic criteria of androgen deficiency, as well as the risks and benefits of androgen supplementation in elderly men.

Male hormone replacement therapy implies, of course, that elderly men have a significant deficit in male hormone. Therefore, the first question to be answered is whether the common occurrence of the age-associated decline of testosterone levels is inherent to the aging process and occurs also in healthy men or whether the observed decline is the consequence of intercurrent disease, obesity, stress, relative physical inactivity or medications, etc.

After years of controversy, due to differences in the characteristics of the population studied and variation in the timing of blood sampling (morning or afternoon) or the frequently small number of elderly subjects studied, authors now agree that in healthy men also there is a clear, slow but continuous, age-dependent decline of testosterone (T) levels, which is more pronounced for free T (FT) than for total T, a consequence of the age-associated increase of the levels of sex hormone binding globulin (SHBG); at 75 yr of age mean total T level in the morning is about two thirds of the mean level at 20 -30 yr of age, whereas the mean FT and bioactive T (FT plus albumin bound T) level are only 40% of the mean levels in younger males. Moreover, the circadian rhythm of plasma T levels, with higher levels in the morning than in the evening, is generally lost in elderly men (3). However, wide interindividual variations exist due to genetic factors, body mass index, diet, social habits (alcohol, tobacco), and stress, and about 20% of males over 70 yr old have T levels in the upper third of males 20-40 yr of age (4). This is in clear distinction to the situation in postmenopausal women who all have clearly decreased estradiol levels. It is important to mention that this decrease, observed in cross-sectional studies, has now been confirmed by longitudinal studies (5-9). However, the androgen deficiency in elderly men is generally moderate; therefore, some authors have suggested the term partial androgen deficiency in the aging male (PADAM). Others, in analogy with the term menopause in women, use the term andropause, although distinct from women in menopause, elderly men retain their reproductive capacity.

Although the decrease in (F)T levels occurs in healthy elderly men, it is evident that sequelae of intercurrent disease (10), medication, environmental, psychosocial, and socioeconomic factors accelerate this age-associated decrease. Recently, the important role of abdominal obesity in the age-associated decrease of T levels has been stressed (10-12).

Androgens have many physiologic actions, but does the age-associated decrease in (F)T levels have clinical significance, and does it indicate hypogonadism? Evidence for the clinical significance could be provided by the eventual similarity between signs and symptoms of aging and androgen deficiency, respectively, in young men, the existence of a significant correlation between symptoms and (F)T levels, and the eventual beneficial effect of androgen supplementation in elderly men with low T levels.

Similarity of Signs an Symptoms of Aging and Androgen Deficiency, Respectively, in Young Men.

The age-associated decrease in muscle mass and strength, energy and work capacity, body hair, and hematopoiesis; the decrease in sexual drive and activity, bone mass, and cognitive function; the decline of memory and of the sense of general well being; the difficulties in concentration; and the increase in abdominal fat mass are reminiscent of the symptomatology of androgen deficiency. However, these symptoms are multifactorial in origin; aging is accompanied by a decrease of almost all physiological functions and, as far as the endocrine system is concerned, by a decrease not only of gonadal and adrenal androgen secretion but also of GH secretion. Moreover, the age-associated decrease in physical activity is partly responsible for the decrease in muscle mass and bone mineral density (BMD) (13). Hence, it is not surprising that the correlation between aging symptoms and T levels is often rather poor.

Correlation Between Aging Symptoms and (F)T Levels.

Whereas the age-associated decrease of BMD with an exponential increase in bone fracture rate with age (14, 15) is well established, the role of the partial androgen deficiency in aging males in this decrease remains to be established (16). Indeed, available data are equivocal, some studies showing a significant, albeit weak, association between FT levels and BMD at some but not all bone sites (13,17,18), whereas others did not find any correlation (19-21). Recently, several large-scale studies, involving several hundreds of elderly men (22-24), found bio-T to be significantly associated with bone density at radius, spine and hip; however, the correlation with bioavailable estradiol, the levels of which decline in elderly males, was even stronger, suggesting that part of the androgen effects on bone are at least partially indirect, mediated via their aromatization (25). Nevertheless bio-T also was correlated with all regions of proximal femur BMD and total body BMD after adjustment for age (24). Barrett-Connor et al. (26) observed a significant negative graded association between levels of total and bioavailable estradiol but not bio-T and fracture prevalence in males (median age 67 yr, range 56-87 yr) independently of age, body mass index, or exercise.

On the basis of these recent large-scale studies it seems reasonable to accept a role of the decreased T levels in the age-associated osteopenia. Aging is also accompanied by a increase in abdominal fat mass and a decrease of muscle mass. We (27) as well as Seidell et al. (28) and Tchernof et al. (29) observed abdominal fat mass to be inversely correlated with FT, independently of age. Visceral fat accumulation is highly significantly associated with increased risk of cardiovascular disease, impaired glucose tolerance, and non-insulindependent diabetes mellitus (syndrome X) (30, 31). Whether the abdominal obesity is the consequence of the low T levels or vice versa is not clear. Indeed, obesity induces a decrease of T levels via a decrease in SHBG levels, and morbid obesity (BMI >35) also induces a decrease of FT (11).

The age-associated decline in muscle mass (12 kg between 20 and 70 yr of age), which is most pronounced for the fast twitch type II fibers (32), is a major contributor to the ageassociated decline in muscle strength and early onset of fatigue (33) and a strong predictor of falls, fractures, and loss of independent living. In fact, maximal muscle strength correlates with muscle mass independently of age (34).

Whereas van den Beld et al. (24) observed that in men 73-97 yr of age, serum T levels were, independently of age,positively related to isometric grip strength and leg extension strength, and Abassi et al. (35) observed a correlation between T levels and severity of loss of muscle function in
institutionalized men who have lower T concentrations than healthy elderly men, Baumgartner et al. (36) observed in elderly men (65-97 yr old) a significant correlation between FT and muscle mass, but not grip strength. Verhaar et al.(37), similarly, did not find any association between T levels and muscle strength.

It should be stressed that although a correlation exists between the lower T concentration and reduced muscle function in older men, T is not the only factor responsible for the age-associated muscle loss.

The prevalence of atherosclerosis in men increases spectacularly with aging. In the view of the higher prevalence in men than in women, the decrease of high density lipoprotein cholesterol (HDL-C) levels at puberty in boys (38), the atherogenic lipid profile in hirsute women, and the sporadic reports of premature cardiovascular disease in athletes abusing anabolic/ androgenic steroids, this difference is generally considered to be related to the higher androgen levels in men. Nevertheless, the vast majority of crosssectional studies show a positive correlation between FT levels and HDL-C (39-41) and a negative correlation with fibrinogen, plasminogen activator inhibitor-1 (42), and insulin levels as well as with coronary heart disease (43, 44), but not with cardiovascular mortality (45-47). However, the correlation between T levels and HDL-C and insulin sensitivity is only observed within the physiologic male concentration range of T (48, 49). Androgen blockade by GnRH leads to an increase of HDL-C and, to a lesser extent, of total cholesterol, the effect of which is neutralized when T enanthate was injected in parallel, to maintain physiological T concentrations (48), whereas supraphysiological T levels induce an increase in low density lipoprotein cholesterol (LDL-C) and a decrease of HDL-C (40) Moreover, it should be realized that, beside the effects on lipids, T has direct
effects on several vasoactive factors such as endothelin (50), prostacyclin, and thromboxane A2 (51).

The inverse correlation between T levels and the severity of coronary artery disease as reported by Phillips et al. (43), may be related to the fact that low androgen levels are accompanied by an accumulation of abdominal visceral fat (28, 29), which is known to be associated with increased cardiovascular risk factors (52), and Tchernof et al. (29) observed that upon multivariate analysis, adjusting for visceral obesity, the correlation between androgen levels and lipid parameters lost its significance.

As to the role of the age-associated decline in T levels in the highly negative correlation between sexual desire, arousal, activity, and age, Schiavi (53) reported that men desiring intercourse with a greater frequency than once a week, had higher T levels than men with lower frequency. Moreover they observed (54) that men with the primary diagnosis of hypoactive sexual desire had significantly lower T levels than controls. Similarly, Pfeilschifter et al. (55) reported that men with greater sexual activity had higher bio-T levels than men with a lower frequency and they conclude that androgen deficiency may contribute to the age-related decline in male sexuality. Nilsson et al. (56) finally, in an epidemiological study of 500 51-yr-old men, observed that low levels of bio T were associated with low sexual activity.

However, other authors (57, 58) did not observe any correlation between plasma T levels within the normal range and sexual activity. Moreover, it is known that healthy males have much higher T levels than required to maintain sexual function, although Schiavi (53) as well as Bancroft (59) suggested that circulating androgen levels in elderly men might be insufficient to sustain nocturnal penile tumescence and adequate sexual function.

As to erectile dysfunction, which increases dramatically with age, whereas androgens, acting both centrally and peripherally (60) are essential for normal penile erection and T-stimulating nitric oxide synthesis in the corpora cavernosa (60, 61), androgen deficiency is rarely the major cause of
impotence in elderly males, although it may play a subsidiary role. There is good evidence that, whereas nocturnal penile tumescence is androgen dependent, erection in response to visual erotic stimuli is androgen independent (62). Davidson et al. (63) suggested that the effects of T may be mediated via changes in genital sensitivity.

Finally there is good evidence for a strong correlation between T levels and cognitive performance such as spatial abilities or mathematical reasoning (64, 65), findings which were confirmed in Western and non-Western groups of healthy males (64). Studies addressing correlations between T levels and cognitive functions specifically in elderly man are not available.

As to the role of T in the depressed mood frequently observed in elderly men, whereas data in the literature are rather divergent [for review see Christiansen (66)], a recent large study by Barrett-Connor et al. (67) involving 856 men age 50-89 yr showed a significant inverse correlation between bioavailable T and a depression score, independent of age and weight.

In summary, many aging symptoms in men are suggestive of androgen deficiency and, in fact, there frequently exists a weak correlation of these signs with plasma T levels; many, but not all, studies show the persistence of these correlations after correction for age.

Nevertheless, it should be kept in mind that most of the aging symptoms are multifactorial in origin and that the age-associated decrease in GH levels might play an important role in the symptomatology (68), because symptoms of GH deficiency in young men and the symptoms of aging again show a striking similarity; decrease in muscle mass, increase in abdominal fat, thinning of the skin, asthenia, and adynamia.

Aging and Adrenal Androgens

Aside from a decrease in the secretion and plasma levels of T, aging is accompanied by a decrease of the plasma levels of the major adrenal androgen, dehydroepiandrosterone sulfate (DHEAS). The age-associated decrease is the most important decrease of all hormones; at 75 yr of age, mean DHEAS levels are only 20% of levels in young adults and, whereas rather important interindividual variations exist, all men and women show an important age-dependent decrease (69-71).

Does this decrease have clinical significance? Although it has been reported that in animals that do not secrete DHEAS, administration of DHEAS generally in pharmacological doses, has antiatherogenic, immunostimulatory, and anticarcinogenic effects, the effects of DHEAS in man remain questionable. Functional parameters of daily living in the oldest males were reported to be lowest in men with the lowest DHEAS levels (72), whereas data of Abassi et al. (73) show that men with higher DHEAS levels appear to be more fit and leaner than men with lower DHEAS levels. This, of course, does not indicate a causal role of DHEAS in physical fitness or general well-being. Moreover, it has been reported that men with low DHEAS levels would be at higher risk of cardiovascular mortality within the next 2 yr (74,75), but this has not been confirmed (76,77). Finally, the increase in physical well-being after DHEAS administration reported by some authors (78) was not confirmed by others (79), but there is some evidence that DHEAS administration to men with Addison’s disease improves general well-being (80, 81).